Organic isothiocyanate fungicides



ORGANIC ISOTHIOCYANATE FUNGICIDES Herbert Aubrey Stevenson, John RayMarshall, and Anthony Frederick Hams, all of Nottingham, England,assignors to Boots Pure Drug Company Limited, Nottingham, England, aBritish company No Drawing. Filed Feb. 4, 1957, Ser. No. 637,865

Claims priority, application Great Britain Feb. 24, 1956 15 Claims. (Cl.167-30) This invention relates to the discovery of unexpected valuableproperties in certain organic isothiocyanates and to new fungicidalcompositions containing these com pounds as active ingredient.

The invention consists in compositions for use in horticulture whichcontain as active ingredient a compound having the general formula:

in which R and R each represent a p-isothiocyanato radical and Xrepresents an -S-- or an SO group or R represents p-chlorine, Rrepresents a p-isothiocyanato radical and X represents an -SO group or Rand R each represent a m-isothiocyanato radical and X represents an -$Ogroup.

Certain of the compounds falling within the above general Formula I arenew and these new compounds are di-4-isothiocyanatophenyl sulphoxide,4-chlorophenyl 4- isothiocyanatophenyl 'sulphone anddi-B-isothiocyanatophenyl sulphone. 7

We have now found that dusts, dispersions, emulsions, smokes andaerosols of the compounds of the above general Formula I have propertieswhich render them valuable for the control of fungi for example Venturiainaequalis, Botrytis cinerea, Sclerotinia fructigena,'Tilletia caries,Pyzhium debaryanum, Corticium solani, Podosphaera leucotricha andCladosporium fulvum.

Our invention consists therefore in the new compoundsdi-4-isothiocyanatophenyl sulphoxide, 4-chlorophenyl 4-isothiocyanatophenyl. sulphone and di-3-isothiocyanatophenyl sulphoneand in compositions which contain as active ingredient a compound of theabove general Formu-' 1a I together with a diluent or carrier.

The active compounds of the invention may be prepared by methods whichare well known in the art for the synthesis of organic isothiocyanates.Thus these compounds may be prepared by the action of thiophosgene onthe corresponding amines of the general formueach represent a m-aminoradical and X represents an P-SO group. The thiophosgene may be used assuch States Patent 0 2,937,970 Patented May 24, 1960 ice or prepared insitu preferably by reduction of trichloromethane sulphenyl chloride withstannous chloride as described by Connolly and Dyson (J.C.S., 1935, p.679).

The dispersions having a solid dispersed phase according to theinvention may comprise the active ingredient in combination with adispersing agent and/or a suspending agent in aqueous medium. Forconvenience the preparation may consist of active ingredient admixedwith a dispersing agent and/or a suspending agent such that a dispersionis formed when the mixture is added to water. To facilitate theformation of a dispersion in this manner, the preparation to be dilutedmay also contain a water-miscible organic solvent, for example, acetone.The dispersions according to the invention also include suspensions inwhich the solid dispersed phase is admixed with an aqueous oil emulsion,the active ingredient being substantially insoluble in the oil thereof,which oil is preferably a non-volatile oil, for example, liquidparafiin. In such compositions the diluent or carrier comprises adispersing and/or suspending agent, an emulsifying agent and anon-volatile oil.

The emulsions according to the invention may comprise the activeingredient in combination with an emulsifying agent and organic solvent,for example, xylene or'an aromatic solvent boiling within the range -300C. It may be advantageous to add a non-volatile vegetable or mineral-oilsuch as liquid paraflin to act as an activator and/or sticker. Theemulsion composition according to the invention may also contain awetting agent. For convenience the composition may consist of the activeingredient admixed with or in solution in an organic solvent ashereinbefore specified together with an emulsifying agent, and ifdesired, a wetting agent such that an emulsion is formed on admixing thecomposition with water. Such compositions also form part of the presentinvention. The aqueous dispersions and emulsions herein described may bediluted with water before application to obtain a final concentration oftheactive ingredient within the range 0.001-10% w./v. but the inventionis not limited to compositions which contain this concentration of theactive ingredient; .the concen tration of the solutions which areemployed depends upon the requirements of the particular sprayingmachine which is to be used.

Dispersions of the active ingredient in which the carrier is apulverulent solid diluent also form part of the present invention, Suchdispersions may contain up to 50% w./v. of the active ingredient.

We have found that it is possible to employ a compound having the abovegeneral' Formula I in the form of smokes and aerosols. This method ofapplication is very convenient when the plants, whichit is desired totreat for the control of the fungi, are located in an enclosed area, forexample, in a greenhouse. Accordingly our invention also comprisescompositions for the preparation of fungicidal smokes and aerosols whichcontain as active ingredient a compound of the general Formula I.

In the preparation of compositions suitable for dispersion as aerosolswhich contain as active ingredient compounds of the above generalFormula I, the active ingredient may be dissolved in a volatile solventsuch as acetone. Alternatively the active ingredient may be dissolved ina high boiling aromatic solvent such as xylene or a non-volatile oilsuch as vegetable oil together with a supplementary solvent suchascyclohexanone'or acetone if desired. Such compositions are readilydispersed as aerosols either by mechanical means or by incorpora'tingtherein a volatile'propella'nt such as Freon (a mixture of chlorofluoroderivatives of methane and ethane).

Compositions suitable for the generation of fungicidal smokes comprisethe active ingredient in association with an ignitible slow burningcomposition such that a smoke containing the active ingredient isgenerated on ignition. The wetting and emulsifying agents which areemployed inthecompositionsof the invention should preferably be free ofamino groups and alcoholicgroups'so as to avoid the possibility ofcondensation taking place between the active ingredient and one of theaforementioned groups with the formation of thioureas and thiourethanesrespectively.

In the case of compositions which are to be subjected to prolongedstorage and which contain a compound having the above general Formula 1dissolved in an organic solvent the latter should preferably besubstantially anhydrous as the presence of water in such solutions tendsto cause hydrolysis of the active ingredient on storage.

Other insecticides and fungicides such as D.D.T. ben zene hexachlorideand sulphur may beincorporated in the compositions of the inventionbefore application of the latter to the plants.

Compounds having the above general Formula I have been demonstrated topossess fungicidal activity in tests carried out in the followingmanner.

LABORATORY TEST (1) Spore germaninatz'on Iest.The test is based on therecommendations of the American Phytopathological Committee (1943). On aglass slide a deposit of known weight of the compound under test isformed by allowing an acetone solution of known concentration of thecompound to evaporate. Spores of one of a number of pathogenic fungi inaqueous suspension are set on these deposits to germinate and thepercentage germination is noted. In Table I the results of these testsare shown, the approximate L1). 50" being the concentration in parts'per million of the acetone solution of the substance under test whichit is calculated would inhibit 50% of the spores from germinating; thehigher the value of the L.D. 50 the lower the activity of the compound.The figures shown in the column headed Derived LB. 50 are obtained bysuspensing spores in a series of solutions of graded dilution of thesubstance under test and assessing the concentration causing 50%inhibition of germination. The test solutions are prepared by dilutionwith water of a 5% w./v. solution of the substance in acetone. In TableI thesymbols B.C., S.F., CF. and V.I. represent the fungi Bot'rytiscinerea,-Sclerotinia fructigena, Cladosporium fulvum and Venturiairzaequalis respectively.

Table 1 Approximate L1). 50 Derived LB. 60 Compound 7 13.0. 8.1. 0.1:.V.I. V.I. Gi 8.1

Di-4-isothiocyanatophenyl sulphuric--. 300 12 6 1 0. 094chloropheny1-4-isothiocyanatophenyl v e sulphone 400 80 2 1 0. 14Di-3-isothiocyanatopheny1sulphone--..- 3 2 12 1 0.20Di-tisothiocyanatophenyl sulphoxide--. 1 1 1 1 0.19 0.05 0.11

(2) Bum of wheat test-A number of the compounds of the invention havebeen tested in the following manner. Seeds of wheat are infected withTilletia caries and dressed with dusts containing w./v. of the substanceunder test in kaolin at the rate of 2 ozs. of dust per bushel of seed.The dressedseeds are incubated for 5 days on agar and at the end 'ofthis time the seeds are removed from the agar and the spores of "thefungus remaining on the agar surface are examined for germination. Theresults obtained in this testare shown in Table ll.

Key: 0 complete control.

EXTENSION TESTS The compounds have been subjected to further tests whichare designed to ascertain the activities of the compounds againstvarious fungiliving on a plant host.

(1 Tomato leaf mould (Cladosporz'um fulvum) .-This test is carried outusing young tomato plants growing in pots in a glasshouse. A group offive tomato plants is sprayed to run off with an aqueous suspensioncontaining 0.05% w./v. of the compound under test. When the spraydeposit is dry the plants are enclosed in a chamber in a moistatmosphere at a temperature of 75 C. and the plants are inoculatedwithsp'ores of Cladosporium fulvam. A group 'ofuntr'eated plants isinoculated in similar manner. The plants are kept under these conditionsfor 3 days and are then kept under normal glasshouse conditions for '1518'days At the end of this time three leaves are removed from each plantand examined; the number of lesions per leaf is counted. The averagenumber of lesions per leaf in the treated plants is expressed as apercentage of the average number of lesions per leaf in the untreatedcontrol. plants and this figure is designated percentage infection.

Substances which show activity in the above spray test are submitted toa further test which employs the active substance in the form of anaerosol. A group of five young tomato plants is placed in a fumigationchamber of a volume of 11 cu. ft. and 0.125 cc. of a 5% w./v. solutionin acetone of the substance under test is dispersed into the chamber bymeans of a. paint spray gun. The aerosol cloud is allowed to settle for3 hours after which the plants are removed from the fumigation chamber,inoculated with spores of Cladosporz'am falvum and the infectionassessed as described above in the spray test. The results obtained inthe above two tests are summarised in Table III. p p (2) Graandselmildew.ln this test groups of 5 groundsel plants growing in pots in aglasshouse are sprayed to run off with an aqueous suspension containing0.05% w./v.; of the compound under test and as soon as the spray depositis dry the plants are artificially infected with Oidium sp. undersimilar conditions to those described in the Tomato leaf mould test. Thedegree of control of the mildew by the treatment is assessed by a visualexamination of the plants and the results are expressed in Table III onan arbitrary scale of very good control (VG),

.good control (G), fair control (F) and poor control (P).

(3) Apple mildew (Podasplzaera leuc0tricha).This test is carried out ina similar manner to that described above for grounds'el mildew employingapple seedlings growing inputs in a glasshouse. The results areexpressed in Table III in like manner to those obtained in the Groundselmildew test.

(4) Apple scab (Venturia inaequalis).-The activity of the compounds ofthe invention has been assessed by a small scale field trial carried outas follows. In this trial the trees were two year old Bramleys plantedclose together in a nursery and randomised blocks each containing fourtrees were used for each substance under test. The trees were sprayed torun olf six times between April and July 1956 with aqueous suspensionscontaining 0.1% w./v. of active ingredient. An assessmerit of theeffectiveness of the compounds under test was made in the middle ofAugust by collecting leaves from each tree and measuring'the percentagearea of each infected by the fungus. The results quoted in Table IIIbelow are averages of the percentage areas infected on the 400 leavescollected from each block of trees. For the purposes of comparisoncontrol blocks of trees which received no treatment were similarlyexamined, the average degree of infection in the controls 6 80l00 C.),isolated by filtration and recrystallised from petroleum ether (boilingrange '80 100 C.). There is thus obtained di-3-isothiocyanatophenylsulphone which is identical with the product obtained in 5 (a) above.being 1.2%. EXAMPLE 3.

(5) Celery leaf sp'ot.The activity of some of the (a) In the preparationof di-4-isothiocyanatophenyl compounds against Septorz'aapii-graveolentis on celery sulphoxide, a solution of 11.6 grams ofdi-4-arninoplants was determined in a similar manner to that dephenylsulphoxide in 50 cc. of 2 N hydrochloric acid scribed for the first ofthe Tomato leaf mould tests. is stirred at room temperature with asolution of 9.5 The results are summarised in Table III and expressedcc. of thiophosgene in 100 cc. of chloroform. An exoin the same manneras those obtained in the Tomato thermic reaction takes place and 100 cc.of water is leaf mould tests. added to the reaction mixture toreduce thetemperature.

Table III Tomato Leaf Mould Celery Lea! (percent infection) GroundselApple Apple Scab Spot Compound Mildew Mildew (percent (percentinfection) infection) Spray Aerosol t Di-4-isothiocyanato-phenyl sul- 7phone 3 12 P 0.49 6.6 4-Chlorophenyl 4-isothiocyanatophenyl sulphone 012 G F 1.39 Di-3 isothiocyanatophenyl sulphone 100 7 P 0.78 3.2

The following non-limitative examples illustrate the After stirring for50 minutes, the chloroform layer is invention. separated, dried overanhydrous sodium sulphate and EXAMPLE 1 evaporated. The crystalline'residue is extracted with In the preparation of 4-chlorophenyl4-isothiocyanato- 200 cc. of boiling petroleum ether (boiling range 100-phenyl sulphone a mixture of 13.4 grams of 4-arnino- 120 C.) and thesolution so obtained is decanted from phenyl 4-chlorophenyl sulphone,8.4 grams of thiosphosremaining solid. On cooling to room temperaturedi-4- gene and 50 cc. of chloroform is heated under refluxis-othiocyanawphenyl sulphflxide cfystallises and is for 20 h At th d fthi ti th olutio so lected by filtration. This extraction procedure isreobtained is filtered and 1 gram of active alumina and peeled twicemore, sing as solvent the mother liquor 150 cc. of petroleum ether(boiling range 80-100 (3,) from the previous crystallisation. There isthus obtained are added to the filtrate which is then filtered at thedi-4-isothiocyanatophenyl ulphoxide in the form of a boiling point. Thecrystalline solid which separates crystalline solid which has a meltingpoint of 138-140 from the filtrate on cooling is isolated by filtrationand (Foundi 14H80N S requires C, recrystallised from a mixture of equalvolumes of chloro- 53.2; H, 2.5%.) form and petroleum ether (boilingrange 80-l00 C.). Alternatively this compound yp p as There is thusobtained 4-chlorophenyl 4-isothiocyanato- S- To a mixture of 11.6 gramsof di-4-aminophenyl sulphone in the form of a crystalline s lid hi hphenyl sulphoxide, 11 cc. of trichloromethanesulphenyl has a meltingpoint of 149 C. (Found: C, 50.1; H, chloride, 50 cc. of alcohol-freechloroform and 50 cc. 2.5. C H O NCIS requires C, 50.4; H, 2. of 2 Nhydrochloric acid, 22.6 grams of stannous chlo- EXAMPLE ride is addedwith stirring. The temperature of the reactlon mixture 1s not allowed toexceed 45 C. The

(a) In the preparation of di-3-is thiocyan p y mixture is stirred atroom temperature for 1 hour, filsulphone a solution of 10.5 cc. ofthlophosg 111 100 tered through kieselguhr and the chloroform andaquecc. of chloroform is added to a suspension of 24.8 grams (ms layersSeparate The hl f layer is dried 0f p y sulphone in 50 (1Q 0f 2 N y overanhydrous sodium sulphate and evaporated to drychlofic acid WithVigorous Potassium Carbonate ness under reduced pressure. The residuethus obtained is added to the mixture with continued Stirring until issubjected to a number of extraction and crystallisathe aqueous layer ispermanently neutral. The chloroti procedures in the same manner to thatdescribed i layer f p rd driedd over ZHISIOUS sldiurn above. There isthus obtained di-4-isothiocyan-atophenyl sup ate an evaporate to ryness.e resl ue ls l h i whi j i recrystallised from trichloroethylene. Thereis thus obabfvg ch denucal Wlth the prompt descnbed taineddi-3-isothiocyanatophenyl sulphone in the form EXAMPLE 4 i of acrystalline solid which has a melting point of 119- a 122 0. (Found: c,50.5; H, 2.5. C H 0 N S reg g 'i g jf gf a i f gi Fwd, Pans quires C,505; 14%.) h c lorop eny -1sot ocyanatophenyl sol.

(b) Alternatively di-3-isothiocyanatophenyl sulphone g i mtlmatey mlxedwith 8 parts by welght of may be prepared'in the following manner. To astirred e 01 (a condensate of fPrmaldehyde and an alkyl mixture of 243grams of di 3 aminophenyl sulphone aryl sulphonate), 5 parts by Weightof Nansa (the sodium 100 cc. of alcohol-free chloroform, 67.6 grams ofstan- Salt of alkyl' arylsulphomc acid) and Parts by Weight nouschloride, 40 cc. of concentrated hydrochloric acid of kaolm- T1115c0111130531011 y be added to Water to and 360 cc. of Water there isslowly added 25 cc. of form a dispersion Suitable r t u tural use.redistilled trichloromethanesulphenyl chloride. The re- EXAMPLE 5 actionmixture isstirred for 1.5 hours, filtered through kieselguhr and thelayers separated. The aqueous layer 70 the Preparatlon of funglcldaldust 5 Parts y is washed with 50 cc. of alcohol-free chloroform and theYvelght of 4'chlorophenyl Y P Y 811119116116 combined chloroformsolutions are dried over anhydrous 1S intimately mixed with Parts yWeight of kaolinsodium sulphate. The chloroform is removed by dis-Compositions similar to those described in Examples tillation underreduced pressure and the residue is slur- 4 and 5 may be prepared inwhich 4-chlorophenyl 4- ried with cc. of petroleum ether (boiling range75 isothiocyanatophenyl sulphone is replaced bydi-3-isothiocyanatophenyl sulphone, di-4-isothiocyanatophenyl sulph-EXAMPLE 7 In the preparation of a dispersible powder 10 parts by weightof 4-chlorophenyl 4-isothiocyanatophenyl sulphone is intimately mixedwith 8 parts by weight of Belloid T.D. (a condensate of formaldehyde andan alkyl aryl sulphonate) and 82 parts by weight of kaolin. Thiscomposition may be added to water to form a dispersion suitable forhorticultural use.

In exactly similar manner there may be prepared a composition whichcontains as active ingredient di-3- isothiocyanatophenyl sulphone.

EXAMPLE 8 In the preparation of a composition suitable for dispersion asan aerosol sufficient 4-chlorophenyl 4-isothiocyanatophenyl sulphone isdissolved in a mixture of parts by volume of arachis oiland 95 parts byvolume of substantially anhydrous acetone to obtain a solution whichcontains 5% w./v. of active ingredient.

This composition is readily dispersed as an aerosol by mechanical means,for example, by the use of a paint spray gun.

Similar compositions may be prepared in which the active ingredient isone of the following compounds:

Di-S-isothiocyanatophenyl sulphone.

Di-4-isothiocyanatophenyl sulphoxide.

EXAMPLE 9 In thepreparation of a composition which is suitable fordilution with water to produce a dispersion parts by weight of4-chlorophenyl 4-isothiocyanatophenyl sulphone is dissolved insufficient acetone containing 1% v./v.. of Ethylan CP (a polyethyleneoxide condensate of octylphenol) to obtain a solution which contains 10%w./v. of active ingredient.

EXAMPLE 10 In the preparation of a composition which is suitable fordilution with water to produce a stable emulsion sufiicientdi-3-isothiocyanatophenyl sulphone is dissolved in a mixture of 10 partsby volume of Ethylan SE (a mixture of lauric diethanolamide and apolyethylene oxide condensate of octylphenol) and 90 parts by volume ofbenzene to obtain a solution which contains 5% w./v. of activeingredient.

A similar composition may be prepared using toluene in place of benzene.

We claim:

1. A fungicidal composition comprising an inert fungicidal adjuvant as acarrier and as the active fungicidal ingredient at least one organicisothiocyanate of a formula selected from the group consisting of andwherein R and R each represent an isothiocyanato radical.

2. A fungicidal composition comprising an inert fungicidal adjuvant as acarrier and as the active fungicidal ingredient at least one organicisothiocyanate selected from the group consisting ofdi-4-isothiocyanatophenyl sulphoxide4-chlorophenyl-4-isothiocyanatophenyl sulphone di-3-isothiocyanatophenylsulphone m di-4-isothiocyanatophenyl sulphone.

3. A fungicidal composition according to claim 1 in which said carrieris a pulverulent solid diluent.

4. A fungicidal composition according to claim 1 containing a dispersingagent.

5. A fungicidal composition according to claim 4 containing a watermiscible organic solvent.

6. A fungicidal composition according to claim 1 containing a dispersingagent, an emulsifying agent, a non volatile oil and water.

7. A fungicidal composition according to claim 1 containing anemulsifying agent and an organic solvent.

8. A fungicidal composition according to claim 7 containing a wettingagent.

9. A fungicidal composition according to claim 1 in which said activeingredient is dissolved in an organic solvent.

10. A fungicidal composition according to claim 9 in which said solventis a low boiling organic solvent.

11. A fungicidal composition according to claim 9 in which said solventis a high boiling organic solvent.

12. A fungicidal composition according to claim 9 in which said solventis a mixture of low and high boiling solvents.

13. A fungicidal composition according to claim 9 containing a volatilepropellant.

14. A fungicidal composition according to claim 1 which contains anignitible slow burning composition so that smoke containing the activeingredient is generated upon ignition of the composition.

15. A method of controlling fungi on vegetation which comprises treatingthe vegetation with a fungicidal composition containing as an activefungicidal ingredient at least one organic, isothiocyanate compound of aformula selected from the group consisting of wherein R and R eachrepresent an i'sothiocyanato radical.

and

References Cited in the file of this patent FOREIGN PATENTS GreatBritain Mar. 11,

1. A FUNGICIDAL COMPOSITION COMPRISING AN INERT FUNGICIDAL ADJUVANT AS ACARRIER AND AS THE ACTIVE FUNGICIDAL INGREDIENT AT LEAST ONE ORGANICISOTHIOCYANATE OF A FORMULA SELECTED FROM THE GROUP CONSISTING OF